Pain as well as other forms of somatosensory stimulation of the face and intraoral cavity can affect the activity of hypothalamic neurons associated with autonomic, neuroendocrine and affective functions. It is the changes in these functions in response to pain that are believed to bring about suffering and impairment of the quality of life. The ability of hypothalamic neurons to respond to painful stimuli of the face suggests that sensory information that originates in structures Innervated by the trigeminal nerve is available to these neurons. Earlier studies have shown several multisynaptic pathways through which brainstem trigeminal neurons may reach the hypothalamus. However, we have recently found that many brainstem trigeminal neurons carry nociceptive information directly to the different hypothalamic regions. Injections of retrograde tracers that were restricted to the caudal hypothalamus labeled about 450 neurons bilaterally within laminae I-II and V of subnucleus caudalis and C1 segment, and in subnuclei interpolaris and oral is. Adjacent to the trigeminal nuclei, many neurons were found in the region Immediately Internal to the lateral part of the medullary reticular formation (subnucleus reticularis ventralis). We have physiologically recorded from 25 trigeminal nucleus caudalis neurons that were antidromically activated from the hypothalamus by a low current. Some of these neurons responded to only noxious mechanical and thermal stimuli applied to their cutaneous receptive field; others responded to innocuous mechanical stimuli as well, but were more strongly activated by the noxious stimuli. Few neurons also responded to electrical stimulation of the dura, mechanical stimulation of the retina and lingual and oral mucous, and chemical stimulation of the nasal mucous. The cutaneous receptive fields were ipsilateral and covered small (restricted to either V1, V2 or V3) and large (V1+V2, V2+V3, or all of them) regions of the face and neck. In the proposed studies we will 1) continue our anatomical studies and determine the projections of all trigeminal nuclei to the different hypothalamic areas, using retrograde and anterograde tracing techniques; 2) continue our physiological studies of trigeminal neurons that project to the hypothalamus and examine to a greater detail their responsiveness to stimulation of external and internal structures In the face and cranium (skin, cornea, dura, vibrissae, oral mucous, nasal mucous etc.), using extracellular recordings and antidromic activation techniques; and 3) determine the locations of trigeminohypothalamic tract axons In the mid brain and diencephalon. These studies will provide important information on brainstem trigeminal neurons that Innervate unique trigeminal structures, and project directly to areas associated with autonomic, endocrine and affective responses to nociceptive and other somatosensory stimuli. As we learn more about the direct projections from the spinal cord and trigeminal nuclei to the hypothalamus, it may be possible to develop an hypothesis about their function. One option to test such an hypothesis will be to lesion the pathway selectively and determine changes in the activity of the target neurons and/or in the behavior of the animal.